Ankita Rao

Background: Congenital cytomegalovirus infection (cCMV) is the most common congenital infection in the United States, caused by vertical transmission of the human cytomegalovirus (HCMV). cCMV can result intrauterine fetal demise, miscarriage, neurodevelopmental disorders, intracranial abnormalities and sensorineural hearing loss¹. Antiviral medications available for treatment of transplant patients cannot be used to prevent cCMV during pregnancy due to teratogenic or toxic side effects¹. Additionally, reinfection by new HCMV strains can occur in patients with convalescent natural immunity prior to pregnancy¹. Consequently, a vaccine must elicit a protective antibody immune response that exceeds natural immunity and can enable transplacental transmission to protect the fetus against cCMV. The viral glycoprotein B (gB) is an envelope glycoprotein necessary for viral entry into all cell types and is a target antigen for strong neutralizing immune responses¹. A gB/MF59 subunit vaccine elicited 50% efficacy in clinical trials for preventing HCMV infection². Another viral glycoprotein complex, called the pentamer complex (PC) mediates cell entry and infection into epithelial and endothelial cells, and has been extensively studied in the Guinea Pig model as an antibody target for neutralization^1,3.

Objective: This review aims to understand current research into the immune responses to HCMV protection as well as the protective immune responses that can be elicited by an mRNA vaccine to improve on the gB/MF59 vaccine in preventing vertical transmission and cCMV.

Search Methods: The articles reviewed were sourced through PubMed, using reference sections to find relevant precursor studies. Articles were narrowed to a time frame of 2019-2025.

Results: Research into serum samples collected from seropositive and seronegative donors found that the elicited neutralizing antibody response to HCMV was strain independent in seropositive “Elite Neutralizers” with enhanced antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis against HCMV virions⁴. Another set of two studies were performed on samples of seropositive maternal sera and fetal cord blood collected from maternal fetal dyad donors^5,6. In the dyads in which vertical transmission was prevented (defined by seronegative fetal cord blood), there was greater HCMV-specific IgG binding, monocyte Fc receptor activation by IgG binding, antibody-dependent cellular phagocytosis, and antibody-dependent cellular cytotoxicity^5,6. To improve on the gB/MF59 vaccine, mRNA-LNP vaccine technology encoding gB was developed and found to elicit more durable and long lasting antibody responses along with gB-specific T-cell responses in a rabbit model⁷. The mRNA-1647 vaccine by Moderna was developed to encode both gB and PC. When compared to gB/MF59, it resulted in long lasting neutralizing and Fc-mediated responses in seronegative vaccinees, and boosted such responses in seropositive vaccinees, while also demonstrating increased ADCC⁸.

Conclusions: Studies have found that neutralizing and non-neutralizing antibody responses are potent in cases of HCMV infection prevention and vertical transmission prevention. Such responses can be elicited by vaccine targeting gB and PC, with mRNA vaccine technology emerging as a potential strategy to confer long lasting protection against HCMV and cCMV.

Work Cited:

1. Pesch MH, Schleiss MR. Emerging Concepts in Congenital Cytomegalovirus. 2022;150(2):e2021055896. doi:10.1542/peds.2021-055896
2. Jenks JA, Nelson CS, Roark HK, et al. Antibody binding to native cytomegalovirus glycoprotein B predicts efficacy of the gB/MF59 vaccine in humans. Science Translational Medicine. 2020;12(568):eabb3611.
3. Roark HK, Jenks JA, Permar SR, Schleiss MR. Animal Models of Congenital Cytomegalovirus Transmission: Implications for Vaccine Development. J Infect Dis. 2020;221(Suppl 1):S60-S73. doi:10.1093/infdis/jiz484
4. Harnois MJ, Dennis M, Stöhr D, et al. Characterization of Plasma Immunoglobulin G Responses in Elite Neutralizers of Human Cytomegalovirus. J Infect Dis. 2022;226(9):1667-1677. doi:10.1093/infdis/jiac341
5. Semmes EC, Miller IG, Wimberly CE, et al. Maternal Fc-mediated non-neutralizing antibody responses correlate with protection against congenital human cytomegalovirus infection. J Clin Invest. 2022;132(16):e156827. doi:10.1172/JCI156827
6. Semmes EC, Miller IG, Rodgers N, et al. ADCC-activating antibodies correlate with decreased risk of congenital human cytomegalovirus transmission. JCI Insight. 2023;8(13):e167768. Published 2023 Jul 10. doi:10.1172/jci.insight.167768
7. Nelson CS, Jenks JA, Pardi N, et al. Human Cytomegalovirus Glycoprotein B Nucleoside-Modified mRNA Vaccine Elicits Antibody Responses with Greater Durability and Breadth than MF59-Adjuvanted gB Protein Immunization. J Virol. 2020;94(9):e00186-20. Published 2020 Apr 16. doi:10.1128/JVI.00186-20
8. Hu X, Karthigeyan KP, Herbek S, et al. Human Cytomegalovirus mRNA-1647 Vaccine Candidate Elicits Potent and Broad Neutralization and Higher Antibody-Dependent Cellular Cytotoxicity Responses Than the gB/MF59 Vaccine. J Infect Dis. 2024;230(2):455-466. doi:10.1093/infdis/jiad593